Parenteral delivery system utilizing a hollow fiber cellular unit

ABSTRACT

A formulation cell consisting essentially of a hollow fiber surrounded by a beneficial agent is disclosed for use in an intravenous delivery system. An intravenous system is disclosed that uses the formulation cell.

FIELD OF THE INVENTION

This invention pertains to a parenteral delivery system. The deliverysystem comprises a reservoir containing a parenterally administrablefluid, a drip chamber and a cellular unit. The unit houses at least onehollow fiber that is surrounded in at least a part of the exterior areaoccupied by the hollow fiber by a parenterally administrable beneficialagent. The parenteral delivery system is useful for administering abeneficial active agent to a recipient.

BACKGROUND OF THE INVENTION

The parenteral administration of beneficial agents to a needy recipientis a well-accepted and established clinical practice. Presently, abeneficial agent often is administered by using a parenteral deliverysystem. The parenteral delivery system comprises a formulation chambercontaining an active agent, that is mixed with an incoming parenterallyadministrable fluid to form an administrable fluid agent formulation.The fluid is supplied from a fluid container suspended above theformulation chamber. While the form of parenteral administration iswidely used and can lead to acceptable therapy, there is still a greatdeal of dissatisfaction with this kind of delivery system that lendsitself to improvement. Mainly, the value of the system can be improvedand its therapeutic usefulness increased if (1) a means and method aremade available for governing the rate of introduction of active agentinto an intravenous fluid; and, (2) a means and method are madeavailable for governing the rate of introduction of active agent into anintravenous fluid coupled with means for controlling the flow rate ofthe fluid agent formulation to a recipient.

DESCRIPTION OF THE INVENTION

It is immediately apparent, in view of the above written discussion,that a critical need exists for a parenteral delivery system thatovercomes the dissatisfaction associated with the prior art. Theinvention of this application provides a practical and useful solutionto the above problem. That is, this invention makes available aparenteral delivery system comprising; (1) a formulation cellular unithousing a hollow fiber, or a hollow fiber, arrangement that is a meansfor introducing a beneficial agent into a medical fluid, and whichparenteral delivery system also is; (2) a means for governing the fluidflow rate of the fluid agent formulation to a recipient. The deliverysystem delivers a beneficially effective amount of beneficial agent bythe combined operation of the hollow fiber providing a means forreleasing a beneficial intravenously agent and by the rate of flow ofintravenously administrable fluid through the cellular unit.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a parenteral delivery system provided bythe invention;

FIG. 2 is an opened view of a cellular unit housing a plurality ofhollow fibers and a beneficial active agent as provided by theinvention;

FIG. 3 is an exploded view of a spiral wound module for use in thecellular unit;

FIG. 4 is a view of the exploded spiral wound membrane-permeation spiralmodule of FIG. 4;

FIG. 5 is a perspective view of another parenteral delivery systemprovided by the invention comprising a fluid bypass for circumventingfluid flow around a formulation cell; and,

FIG. 6 is a perspective view of another parenteral delivery systemprovided by the invention comprising the formulation cell in a fluidpath that circumvents the main fluid flow path.

The accompanying drawing figures are not drawn to scale but they are setforth to illustrate various embodiments and structural parameters of theinvention. In the drawing figures and in the specification, like partsin related drawing figures are identified by like numbers. The termsappearing earlier in the specification are described hereinafter.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 represents a parenteral delivery system 10 provided by theinvention and designated by the numeral 10. Parenteral delivery system10 of FIG. 1 comprises a reservoir container 11 of a medical fluid 12acceptable for parenteral administration including intravenousadministration. Reservoir 11, in the illustrated embodiment is acontainer made of plastic and it is understood the container can be madeof other acceptable materials such as glass. Reservoir 11 in theembodiment made of plastic comprises a flexible, or a semi-rigid,preferably transparent material such as a non-toxic polyolefin,polyvinyl chloride, or the like. Reservoir 11 is connected to the restof delivery system 10 through connecting spike 14. Spike 14 is hollowand it pierces plastic bag 11 at end. The other end of spike 15 isconnected to a section of medical grade tube 16 that passes through aflow regulator clamp 17 and enters a drip chamber 18. Spike 15 and tube16 convey medical fluid 12 into drip chamber 18 wherein it proceedsdropwise in said drip chamber 18.

Medical fluid 12 is typically a sterile solution, such as a solution ofdextrose, a solution of an electrolyte, or saline. Medical fluid 12 alsois a pharmaceutical vehicle for parenteral administration, and it is apharmaceutically acceptable, non-toxic carrier for a beneficial agent,including a drug to be administered to a recipient. The term drugembraces parenterally administrable drug and intravenously administrabledrug.

Drip chamber 18 is preferably transparent and in this embodiment it ismade of clear glass or plastic. Drip chamber 18 is used to trap air, andit is used in cooperation with regulator clamp 17, for adjusting therate of flow of medical fluid 12 from reservoir 11 as the flow proceedsdropwise through system 10. Drip chamber 18 is connected through tube 19to a formulation cell 20.

Formulation cell 20, as seen in FIG. 1, is a cellular unit sized, shapedand structed for use in a parenteral delivery system. Formulation cell20 is self-contained, self-priming, self-powered and amenable to lowcost manufacture. Formulation cell 20 is light-weight and disposable.Formulation cell 20 is provided with a receiving inlet 21 for receivingincoming tube 19, and it is provided also with an outlet 22 forreceiving outgoing tube 23. Formulation cell 20 is provided with a wall24 that surrounds and forms an internal space, not seen in FIG. 1.Formulation cell 20 is closed at end 21 by closure 25 that fits snuglyinto formulation cell 20, and it is closed at its other end 22 byclosure 26. Tubing 23 is connected to a skin-piercing means 27, such asa needle, for administering a fluid agent formulation to a recipient.Formulation cell 20 is made of glass or plastic, preferably of atransparent glass or plastic for viewing its internal contents.Formulation 20 is optionally equipped with an air vent 28.

FIG. 2 depicts formulation cell 20 in opened section with wall 24 openedat 30. In FIG. 2, wall 24 surrounds and defines an internal space 31.Space 31 contains at least one hollow fiber 32, or space 31 contains amultiplicity of hollow fibers 32, that comprise a bundle of hollowfibers. Space 31 can also house spiral wound module discussed in figurespresented hereinafter. Hollow fibers 32 are supported at their terminalends 33 and 34 by passing through and being suitably held by a pair ofheader support means 35 and 36. Header support means 35 and 36 arejoined to the internal surface 37 of wall 24 by means of a suitableadhesive or cement, resin or the like. An adhesive seal also can be usedto attach the ends of hollow fibers 32 to header means 35 and 36. Bothheader means 35 and 36 are seen in FIG. 2, and header 36 means isdepicted in cross section. The headers are made of a materialsubstantially impermeable to the passage of a beneficial agent andmedical fluid. In this way, the internal space between the headers formsa fluid tight space within formulation cell 20. Each of the hollowfibers 32 in space 31 has the same or about the same length. In apresent embodiment, it is generally desirable for the other dimensionedparameters of the hollow fibers, for example, outside diameter and wall39 thickness to be about the same, although if desired, hollow fibers ofdifferent individual diameters and wall thickness can be used forachieving different results. The hollow fibers generally have a uniformbore 40 or lumen, although hollow fibers possessing different bores arewithin the scope of this invention. Hollow fibers 32 are surrounded inspace 31 by beneficial active agent 38, and space 31 also providessufficient area for fluid 11 and a fluid composition formed in situ inspace 31 or beneficial agent solution to pass around the exterior wallsurface of the multiplicity of hollow fibers.

In operation, parenteral delivery system 10 of FIG. 1 and itsformulation cell 20 as seen in FIG. 2, operate by medical fluid 12flowing from reservoir 11 through medical tube 16 into drip chamber 18.Medical fluid 12 leaves drip chamber 18 through tube 19 and entersformulation cell 20. In cell 20, fluid 12 flows directly into hollowfibers 32 and outwardly through wall 39 of hollow fiber 32 into space31. In space 31, fluid 12 mixes with beneficial agent 38 to form a fluidbeneficial agent formulation that reenters hollow fiber 32. That is, theagent passes, for example in one embodiment by diffusion, throughpermeable wall 39 of hollow fiber 32 and enters lumen 40 of said fiber.In another embodiment wall 39 can be formed of a microporous materialand the agent can pass through the pores thereof. The fluid agentformulation then flow from cell 20 into tube 23 for administering to arecipient through skin-piercing member 27.

In another embodiment provided by the invention incoming fluid 12 entershollow fibers 32 and permeates by osmosis through wall 39, particularlywhen wall 39 is formed of a semipermeable material, into space 31 todissolve beneficial agent 38 and form an agent solution. The agentsolution is then hydrodynamically pumped by osmosis through one or morepassageways 36a in header 36. Alternatively, the osmotic pumping processcan operate by pumping the drug solution through an optional opening 39ainto hollow fiber 32 into lumen 40 and exiting at terminal end 40.

FIG. 3 illustrates another hollow fiber arrangement that can be housedin formulation cell 20. The hollow fiber arrangement illustrated in FIG.3 comprises a spiral wound module 9 seen in exploded view. Spiral woundmodule 9 can be used in those applications wherein it is desirable tomaximize the amount of membrane surface that can be placed into thevolume available in formulation cell 20. Spiral wound module 9 comprisesat least one permselective membrane 8 place in contacting positon with aspacer 7 with membrane 8 and spacer 7 wound around hollow fiber 6 havinga lumen 5. Permselective membrane 8 is permeable to the passageway offluid and it is formed of a permselective diffusional, microporous or asemipermeable material. In an example, permselective membrane 8 can beformed of a microporous poly(urethane) composition. Spacer 7 can beformed of a material impermeable to the passage of agent, such as acloth. The arrows in the figure indicate the flow of agent throughmembrane 8 with the permeate passing into hollow fiber 6. The permeatecan pass through wall 3, formed of a fluid and agent solution materialthat permits passage thereof, of fiber 6; or, the permeate can passthrough orifice 4 in wall 3 and into lumen 5 of hollow fiber 6. FIG. 4depicts a spiral wound module 9 in a wound or closed formation with theadded feature comprising spacer 7 in a corrugated configuration.

FIG. 5 represents another parenteral delivery system 10 provided by theinvention. The delivery system illustrated is similar to the deliverysystem depicted in FIGS. 1 and 2. In FIG. 5, parenteral delivery system10 comprises a primary fluid flow path 41 and a parallel fluid path 42.Primary path 41 comprises reservoir 11 formed as a glass container andsuitably capped for serving as a container for a medically acceptableintravenously administrable fluid. Capped end 43 is connected to tube 15for the flow of fluid into drip chamber 18. Fluid leaves drip chamber 18through tube 44 connected to one entrance port of a Y-site couplingmeans 45. The other distant port of coupling means 45 receives tube 19that passes through flow regulator 46 and connects to formulation cell20. The other port of coupling means 45 is available for receiving tube47 of parallel path 42. Fluid entering formulation cell 20 forms thereina fluid agent formulation that leaves cell 20 through tube 48. Tube 48enters Y-site coupling member 49 that receives outgoing tube 23 foradministering the fluid agent formulation to a recipient via deliverymeans 27. Parallel path 42 comprises tube 47 that passes through flowregulator 50 and enters coupling means 49. Parallel path 42 is a fluidby-pass and it provides a means for letting medical fluid flow by cell20. This is done, by closing flow regulator 46 and opening regulator 50.The by-pass provides for letting fluid flow through the system directly,without flowing through formulation cell 20, thus administeringagent-free fluid to a recipient. The invention illustrated in FIG. 3provides, by regulating fluid or by regulating fluid agent formulationflow, (a) continuous fluid administration, (b) continuous fluid agentadministration, (c) alternating fluid administration and fluid agentadministration, and (d) mixing and diluting of fluid and agentadministration.

FIG. 6 illustrates another parenteral delivery system provided by theinvention. The delivery system illustrated in FIG. 6 uses similar partsas described for FIGS. 1 to 5, and in FIG. 6 they are identified by likenumbers. In FIG. 6, parenteral delivery system 10 comprises a primaryfluid flow path 41 and a parallel fluid path 42. Primary path 41comprises reservoir 11 formed of glass or plastic and capped 43 forserving as a container for a medically acceptable intravenouslyadministrable fluid, capped end 43 is connected to a first section oftube 15 leading to a three-way coupling means 50. Fluid passes throughcoupling means 50 into a second section of medical tubing 51, suitablyequipped with a regulatory clamp 52 and then to three-way clamp 53. Athird section of medical tube 54 conveys the fluid into drip chamber 18wherein the flow rate through parenteral delivery system 10 is dropwiseregulated for administering through tube 23 and delivery member 27 to apatient. Alternatively, a beneficial agent can be added to the medicalfluid by closing clamp 52 and opening clamp 56. These action cause fluidto flow into the parallel path that circumvents the primary path.Parallel path 42 comprises a first section of tubing 57 that passesthrough clamp 56 and enters receiving end 21 of formulation cell 20.Formulation cell 20 houses the hollow fiber arrangement illustrated inFIG. 2. Fluid containing a beneficial agent leaves formulation cell 20through a section of tube 58 that passes through a section of tube 58that passes through open clamp 59. Tube 58 enters coupling means 53,enabling fluid to enter drip chamber 18 and then into tube 23 foradministering to a patient through delivery member 27. FIG. 6 providesin both of its operations, continuous or interrupted, and intervals ofagent-free administration.

Beneficial agent 38 in formulation cell 20 can be in any pharmaceuticalform that leads to a fluid agent formulation by mixing with aparenterally or medically acceptable fluid that enters the cell. The useof formulation cell with agent 38 therein does not require anyreconstituting or admixture prior to use. Exemplary pharmaceuticallyacceptable forms that can be used in cell 20 include solid,microcrystalline, crystalline, particle, pellet, granule, powder, dried,lypophilized and like forms that dissolve, undergo disintegration, andform intravenously administrable solution with a medical fluid. Theamount of agent 38 in cell 20, is a dosage unit amount that leads to apreprogrammed, therapeutic or a beneficial effect. The amount thus is abeneficially effective amount of agent that gives a beneficial or atherapeutic result. Formulation cell 20 generally will have a capacityof from about 10 milliliters to 350 milliliters, or more, and it canhouse from about 0.1 milligrams to 500 grams, or more.

The expression beneficial agent, as used herein, generically denotes anysubstance that produces a therapeutic or a beneficial result, such as adrug, a carbohydrate, an electrolyte, and the like. Intravenouslyadministrable drugs are known in Intravenous Medications, by Sager andBomar, 1980, published by J. B. Lippincott Co., Philadelphia, Pa. Theterm fluid or liquid denotes a fluid or a liquid that can beadministered parenterally including intravenously, comprisingpharmaceutically acceptable carrier for the agent including drug.Exemplary fluids include isotonic saline, Ringer's lactate, and thelike. Intravenous fluids are known in Principles And Practice OfIntravenous Therapy, by Plumer, 1970, published by Little, Brown andCompany, Boston, Mass. The term formulation, and agent formulation aspresently used herein, generically indicates the beneficial agent isformulated, mixed, added, dissolved, solubilized and the like into asolution, or carried in or by the fluid into a physical-chemical formacceptable for parenteral including intravenous administration.

Formulation cell 20 containing beneficial agent 38 contains at least onehollow fiber 32, or a multiplicity of hollow fibers, for the fluid agentcomposition or solution to pass around the exterior wall surface of thehollow fibers, and also for passing through the wall into the lumen ofthe hollow fibers. The fibers in the cell can be in continous relationto each other. The hollow fibers suitable for use herein, can bediffusional, semipermeable or microporous. Suitable materials forforming the hollow fibers include cellulose esters such as celluloseacetate, cellulose diacetate, cellulose triacetate, cellulose formate,cellulose propionate, cellulose nitrate, and the like; also, mono, di,or tri esters and mixtures of such cellulose esters; cellulose etherssuch as methyl, ethyl, hydroxy-alkyl, carboxy-alkyl, and the like; mixedcellulose ethers; regenerated cellulose; acrylonitrile polymers; and thelike. The hollow fibers can be prepared by melt, dry, evaporative, andwet spinning procedures using spinnerettes. For example, a fine hollowfiber of cellulose triacetate is readily produced by a wet spinningprocess in which the ester is dissolved in a solvent, for exampleacetone or methylene chloride, to form a viscous spinning solution. Thespinning solution is extruded into a coagulant bath through the annularspaces in a small annular orifice spinnerette. The extruded fibercoagulates in the desired form of a continously hollow, uniform-walledfiber. Prior to use, the hollow fiber is washed free of any solvent in abath consisting of water. The fibers generally have, in one presentlypreferred embodiment an outside diameter of about 10 to 450 microns, anda wall thickness of about 1 to 100 microns. The formulation cellcontains at least 1 to 10×10⁵ fibers, or more. Microporous hollow fibersare made from materials such as poly(carbonates), poly(amides),styrene-acrylic acids and its copolymers, poly(sulfones),poly(urethane), and the like. The fibers are made as described and alsoby using microporous forming procedures, including cooling a solution offlowable polymer below the freezing point whereby solvent evaporatesfrom the solution in the form of crystals dispersed in the polymer andthen curing the polymer followed by removing the solvent crystals bycold or hot stretching at low or high temperatures until pores areformed, or by leaching from a polymer a soluble component. Proceduresfor manufacturing fibers are known in the Encyclopedia of ChemicalTechnology, by Kirk-Othmer, Vol. 12, 1980, published byWiley-Interscience Co., New York. Header support means 35 and 36, thelatter seen in cross-section, are suitably formed of hydrophobic fluidand agent impermeable materials such as poly(fluorotetratethylene),hexafluoropropylene-tetrafluoroethylene copolymer, and the like.Procedures for manufacturing hollow fibers are disclosed in IndustrialMembranes, by McDermott, 1972, published by Noyes Data Corp., ParkRidge, N.J.

The novel invention uses means for the obtainment of precise control forthe formation of fluid agent formulation in a parenteral deliverysystem. While there has been described and pointed our features of theinvention as applied to presently preferred embodiments, those skilledin the art will appreciate that various modifications, changes,additions, and omissions in the parenteral system illustrated anddescribed can be made without parting from the spirit of the invention.

I claim:
 1. A method for administrating a beneficial drug to awarm-blooded animal, which method comprises the steps of:(a) introducinginto the animal a delivery member in fluid communication with anintravenous delivery system, which system comprises:(1) a reservoir of apharmaceutically acceptable fluid; (2) a formulation cell in fluidcommunication with the reservoir, which formulation cell comprises:(i) awall that surrounds a lumen; (ii) an inlet in the wall for admitting afluid into the lumen; (iii) a spiral wound module in the lumen, saidmodule comprising a permselective membrane wound around a hollow fiber;(iv) a beneficial drug in the lumen in the space formed by the interiorsurface of the formulation cell and the exterior surface of theformulation cell and the exterior surface of the module; (v) an outletin the wall for letting a fluid drug formulation leave the formulationcell, (b) admitting fluid into the formulation cell for contacting thedrug in the space that passes into the spiral wound module for enteringthe hollow fiber to flow from the formulation cell; and, (c)administering the fluid drug formulation flowing from the formulationcell to the animal.
 2. A parenteral delivery system for administering abeneficial agent to a recipient, the delivery system comprising:(a) areservoir of a medically acceptable fluid; and, (b) a formulation cellin fluid communication with the reservoir, the formulation cellcomprising:(1) a wall that surrounds a lumen; (2) an inlet in the wallfor letting fluid into the lumen; (3) a spiral wound module in thelumen, said module comprising a permselective membrane wound around ahollow fiber; (4) a beneficial agent in the space formed by the insidesurface of the formulation cell and the outside surface of the module;and (5) an outlet in the wall for letting a drug formulation leave theformulation cell.
 3. A method for administering a beneficial drug to ananimal, which method comprises:(a) introducing into the animal adelivery member in fluid communication with an intravenous deliverysystem, which system comprises:(1) a reservoir of a medically acceptablefluid; (2) a primary path in fluid communication with the reservoir andthe delivery member; (3) a circumventing path that permits a fluid tobypass the primary path, said circumventing path comprises:(a) aformulation cell, which formulation cell comprises:(i) a wall thatsurrounds an internal lumen; (ii) an inlet in the wall for letting fluidinto the lumen; (iii) a spiral wound module in the lumen, the modulecomprising a permselective membrane wound around a hollow fiber; (iv) abeneficial drug in the lumen in the space between the module and theinside surface of the wall of the lumen; (v) an outlet in the wall forletting fluid and drug leave the formulation cell; (b) admitting fluidinto the formulation cell for contacting the drug to form a fluid drugformulation that passes into the spiral wound module for entering thehollow fiber for flowing from the formulation cell; and, (c)administering the fluid drug formulation flowing from the formulationcell to the animal.
 4. A parenteral delivery system for administering abeneficial agent to a recipient, the delivery system comprising:(a) areservoir of a medically acceptable fluid; (b) a primary fluid path influid communication with the reservoir; (c) a circumventing path thatpermits a fluid to circumvent the primary path, said circumvention pathcomprising:(1) a formulation cell, the cell comprising:(i) a wall thatsurrounds a lumen; (ii) an inlet in the wall for letting fluid into thelumen; (iii) a spiral wound module in the lumen, the module comprisingat least one membrane that permits the passage of fluid and agent woundabout a hollow fiber; and, (iv) a beneficial agent in the lumen in thespace defined by the inside of the wall and the module; and, (v) anoutlet in the wall for letting drug and fluid exit the formulation cell.5. A formulation cell for use with an intravenous delivery system, theformulation cell comprising;(a) a wall that surrounds an internal lumen;(b) an inlet in the wall for letting fluid enter the lumen; (c) a spiralmodule in the lumen, said module comprising at least one membrane thatpermits the passage of fluid and a beneficial agent spiral wound arounda hollow fiber; (d) a beneficial agent acceptable for intravenousdelivery in the cell between the wall and the space surrounding themodule; and, (e) a outlet in the wall for letting agent and fluid exitthe module.